Genetic Variant MTTP:c.2218-235T>C (chr4-99618739-T-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001386140.1(MTTP):c.2218-235T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 152,120 control chromosomes in the GnomAD database, including 6,351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.26 ( 6351 hom., cov: 32)

Consequence

MTTP
NM_001386140.1 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.102

Publications

16 publications found

Variant links:

Genes affected

MTTP (HGNC:7467): (microsomal triglyceride transfer protein) MTP encodes the large subunit of the heterodimeric microsomal triglyceride transfer protein. Protein disulfide isomerase (PDI) completes the heterodimeric microsomal triglyceride transfer protein, which has been shown to play a central role in lipoprotein assembly. Mutations in MTP can cause abetalipoproteinemia. [provided by RefSeq, Jul 2008]

MTTP Gene-Disease associations (from GenCC):

abetalipoproteinemia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, PanelApp Australia, G2P

MTTP links:

ENSG00000248676 (HGNC:):

ENSG00000248676 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 4-99618739-T-C is Benign according to our data. Variant chr4-99618739-T-C is described in ClinVar as Benign. ClinVar VariationId is 1263351.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.433 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MTTP	NM_001386140.1 link	c.2218-235T>C	intron_variant	Intron 15 of 17	ENST00000265517.10	NP_001373069.1
MTTP	NM_000253.4 link	c.2218-235T>C	intron_variant	Intron 16 of 18		NP_000244.2	P55157-1
MTTP	NM_001300785.2 link	c.1969-235T>C	intron_variant	Intron 15 of 17		NP_001287714.2	P55157B7Z7X3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTTP	ENST00000265517.10 link	c.2218-235T>C		intron_variant	Intron 15 of 17	1	NM_001386140.1	ENSP00000265517.5		P55157-1

Frequencies

GnomAD3 genomes

AF:

0.262

AC:

39790

AN:

152002

Hom.:

6333

Cov.:

show subpopulations

Gnomad AFR

AF:

0.437

Gnomad AMI

AF:

0.379

Gnomad AMR

AF:

0.221

Gnomad ASJ

AF:

0.359

Gnomad EAS

AF:

0.189

Gnomad SAS

AF:

0.141

Gnomad FIN

AF:

0.125

Gnomad MID

AF:

0.280

Gnomad NFE

AF:

0.193

Gnomad OTH

AF:

0.257

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.262

AC:

39853

AN:

152120

Hom.:

6351

Cov.:

AF XY:

0.256

AC XY:

19057

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.438

AC:

18156

AN:

41466

American (AMR)

AF:

0.221

AC:

3372

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.359

AC:

1246

AN:

3468

East Asian (EAS)

AF:

0.188

AC:

973

AN:

5180

South Asian (SAS)

AF:

0.140

AC:

678

AN:

4826

European-Finnish (FIN)

AF:

0.125

AC:

1329

AN:

10608

Middle Eastern (MID)

AF:

0.284

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.193

AC:

13125

AN:

67984

Other (OTH)

AF:

0.259

AC:

546

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1399

2798

4197

5596

6995

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

392

784

1176

1568

1960

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.207

Hom.:

3725

Bravo

AF:

0.278

Asia WGS

AF:

0.165

AC:

571

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.71

(source)

DANN

Benign

0.40

PhyloP100

-0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over